The normal morphogenesis of epithelial tissue has been suggested to be controlled by factors derived from mesenchymal cells present around the epithelial tissue. Diseases resulting from the abnormal morphogenesis of epithelial tissue are largely caused by abnormalities of mesenchymal cells. Therefore, an interest has arisen in understanding the mechanism by which mesenchymal cells control the morphogenesis of epithelial tissue.
Epimorphin, disclosed in Japanese Patent Laid-Open Publication No. 25295/94, has 277 to 289 amino acids as a core protein, and has the action of promoting the morphogenesis of epithelial tissue through its action on epithelial cells. It was found that normal tissue formation did not progress when epimorphin failed to function.
Epimorphin has been described in Hirai et al. (1992, Cell, 69:471–481); Hirai (1994, Eur. J. Biochem, vol. 225, 1133–1139); Hirai, et al. (1998, J. Cell. Biol., 140:159–169); and Hirai, et al. (2001, J. Cell. Biol., 153:785–794).
EP 0698666 A2 describes the structure of full length epimorphin as roughly divided into four fragments, beginning from the N-terminus, a coiled coil domain (1), a functional domain (2), a coiled coil domain (3), and hydrophobic domain at the C-terminal. EP0698666A discloses that the functional domain (the domain specified by 104th to 187th amino acids in human epimorphin) participates in cell adhesion and is associated with expression of physiological activity of epimorphin.
U.S. Pat. No. 5,726,298, issued Mar. 10, 1998, discloses human and murine epimorphin nucleotide and amino acid sequences. WO98/22505 and EP 1008603A1 describe polypeptides specified by the N-terminal sequence of the 1st to 103rd amino acids of human epimorphin and by the N-terminal sequence of the 1st to 104th amino acids of murine epimorphin.
Native mammalian epimorphin is almost insoluble in an aqueous media such as saline, which causes difficulty in using epimorphin in compositions for human treatment. Japanese Patent Laid-Open Publication No. 25295/1994 discloses a modified form of epimorphin obtained by removing a hydrophobic region at the C-terminus.
In spite of developments in the understanding of epimorphin and morphogenesis of epithelial tissue, there remains a need for means to modify the morphogenesis of epithelial tissue, in particular as it relates to diseases or disorders associated with abnormal morphogenesis.